CN114557967B - Preparation method of ritonavir solid dispersion - Google Patents
Preparation method of ritonavir solid dispersion Download PDFInfo
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- CN114557967B CN114557967B CN202210265129.XA CN202210265129A CN114557967B CN 114557967 B CN114557967 B CN 114557967B CN 202210265129 A CN202210265129 A CN 202210265129A CN 114557967 B CN114557967 B CN 114557967B
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- 239000007962 solid dispersion Substances 0.000 title claims abstract description 46
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 title claims abstract description 37
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 title claims abstract description 37
- 229960000311 ritonavir Drugs 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 30
- 239000001569 carbon dioxide Substances 0.000 claims abstract description 18
- 229910002092 carbon dioxide Inorganic materials 0.000 claims abstract description 18
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 16
- 229920001531 copovidone Polymers 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 20
- 238000009474 hot melt extrusion Methods 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 12
- 239000013078 crystal Substances 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 6
- 238000002441 X-ray diffraction Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 238000000227 grinding Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 239000007901 soft capsule Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 229940113125 polyethylene glycol 3000 Drugs 0.000 description 2
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108010010369 HIV Protease Proteins 0.000 description 1
- 229940122440 HIV protease inhibitor Drugs 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 108010078762 Protein Precursors Proteins 0.000 description 1
- 102000014961 Protein Precursors Human genes 0.000 description 1
- 108700010756 Viral Polyproteins Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000798 anti-retroviral effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000004030 hiv protease inhibitor Substances 0.000 description 1
- 239000012943 hotmelt Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
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- Virology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Tropical Medicine & Parasitology (AREA)
- AIDS & HIV (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of ritonavir solid dispersion. The method adopts a critical carbon dioxide method to prepare the ritonavir solid dispersion, and prepares the solid dispersion at a lower temperature. Compared with the existing ritonavir hot-melt extrusion process for preparing the solid dispersion, the method can remarkably avoid the generation of impurities in the preparation process.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a preparation method of a ritonavir solid dispersion.
Technical Field
Ritonavir is an anti-Human Immunodeficiency Virus (HIV) drug, which is an HIV protease inhibitor. The indication is that the patients with advanced or non-progressive AIDS are treated singly or in combination with antiretroviral nucleoside drugs. HIV protease is an enzyme found in infectious HIV that cleaves viral polymeric protein precursors into a single functional protein. This effect blocks viral polyprotein cleavage, leading to the formation of immature non-infectious viral particles.
Ritonavir soft capsules and oral solutions were obtained in 1996 and marketed by the FDA in the united states and in the united states, europe, japan and many other countries around the world. Ritonavir soft capsules are approved by the Chinese medicine administration in 1998 at 12 and 18 days, and are acquired from the registration of import medicines. Soft capsules and oral liquids, although guaranteeing a fast release rate of the active ingredient, all require storage under refrigerated conditions. In order to relieve the restrictions of refrigerated storage conditions, the yaban company has developed tablets, and approval of us FDA and eu EMA was obtained in 2010, and the formulation technology thereof adopts hot melt extrusion. With this technique, 2017 ritona Wei Ganhun suspension was FDA approved in the united states. Ritonavir is prepared into solid dispersion by a hot-melt extrusion technology, and active ingredients are dispersed in a carrier in an amorphous mode, so that the dissolution rate is high. In addition, the active ingredient is dispersed in solid, so that the stability of the active ingredient is good under the ordinary room temperature condition, and the active ingredient can be stored under the non-refrigeration condition. Is more convenient for patients.
Ritona Wei Rongdian is 120-122 ℃, which requires the heating temperature of the hot melt extrusion process to be above 100 ℃. Since ritonavir contains 3 amide bonds in the molecular structure, degradation is very easy to occur. Acid hydrolysis impurities are not contained in the raw materials before hot melt extrusion, but the acid hydrolysis impurities are greatly increased after extrusion, and the content limit of the hydrolysis impurities is further widened to 2.6% by the yaban company. Acid hydrolysis impurities have no effect on clinical curative effects, and excessive content can cause adverse reactions.
Compared with the existing hot melt extrusion method for preparing the solid dispersion, the method for preparing the solid dispersion by adopting the critical carbon dioxide method has the advantages that the temperature in the preparation process is lower, and acid hydrolysis impurities are hardly generated in the preparation process.
Disclosure of Invention
The invention aims to solve the problem of stability in the preparation process of the existing ritonavir solid dispersion and provides a preparation method for stabilizing related substances in the preparation process.
The preparation method of the invention comprises the following steps:
the invention provides a preparation method of ritonavir solid dispersion, which comprises the steps of uniformly mixing ritonavir and a carrier in proportion, placing the mixture in an autoclave, introducing carbon dioxide after the set temperature reaches a set value, keeping the temperature and the pressure until the pressure reaches the set value, keeping the temperature and the pressure until the medicine and the carrier are dissolved, and collecting the mixture after decompression to obtain the solid dispersion.
As a preferred embodiment of the present invention, the carrier is polyvinylpyrrolidone or copovidone.
As a preferable scheme of the invention, the mass ratio of ritonavir to the carrier is 1:5 to 1:9.
as a preferred embodiment of the present invention, the temperature set point is 40-50 ℃.
As a preferable mode of the invention, the set pressure is 20-30Mpa.
As a preferred embodiment of the present invention, after obtaining the solid dispersion, the solid dispersion is crushed and passed through a 60-mesh sieve.
Compared with the prior art, the invention has the following optimization steps:
in order to reduce the impurity content of active ingredients in the process of preparing the solid dispersion, the invention selects the type of the carrier, optimizes the temperature and pressure of the carbon dioxide and screens the proper proportion of the carrier and the raw materials after respectively examining the solubility of ritonavir and the carrier in the carbon dioxide under the critical state to prepare the solid dispersion. By screening, amorphous solid dispersion is obtained, and almost no degradation impurity is generated in the preparation process. The prepared solid dispersion can be further processed into tablets, granules, capsules or the like for patients to take.
Detailed Description
The preparation and the effect of the formulation according to the invention will now be further illustrated by the following examples, but the scope of the invention is not limited to the following examples.
Example 1 screening different Carrier species to prepare solid Dispersion
The experimental process comprises the following steps:
(1) Ritonavir, polyethylene glycol 3000, polyvinylpyrrolidone K30 and copovidone in the ratio of 1 to 5 are mixed homogeneously and then placed into an autoclave.
(2) The temperature in each kettle is set to 45 ℃, carbon dioxide is respectively introduced until the pressure reaches 25Mpa, after the preparation time is 5 hours, the solid dispersion is taken out, ground, the crystal forms are detected by adopting an X-ray diffraction method together with the raw materials, and the content of acid hydrolysis impurities is detected by adopting an HPLC method. The results show that the solid dispersion prepared from polyethylene glycol 3000 and ritonavir has high acid hydrolysis impurity content, and polyvinylpyrrolidone K30 or copovidone can be used.
TABLE 1 preparation of crystalline forms and impurity conditions of solid dispersions using different carrier species
The structural formula of the acid hydrolysis impurity is shown as follows, and the acid hydrolysis impurity does not have ritonavir activity and affects ritonavir drug efficacy.
Method for detecting ritonavir impurity acid hydrolysis impurity (import registration standard):
(I) Mobile phase a: phosphate buffer-acetonitrile-tetrahydrofuran-butanol (690:180:80:50), pH was adjusted to 6.3.+ -. 0.1 with 1mol/L phosphoric acid solution or 1mol/L potassium hydroxide solution;
mobile phase B:0.03mol/L dipotassium hydrogen phosphate solution-acetonitrile-tetrahydrofuran-butanol (490:300:130:80);
(II) diluent: 0.03mol/L dipotassium hydrogen phosphate solution-acetonitrile-butanol (80:15:5)
(III) elution procedure:
(IV) chromatography column: c4 reverse chromatography column
And (V) carrying out impurity content statistics by adopting an area normalization method.
Example 2 examination of different proportions of ritonavir and copovidone in carbon dioxide at critical conditions
The experimental process comprises the following steps:
(1) Ritonavir and copovidone are respectively and uniformly mixed according to the proportion of 1:1, 1:3, 1:5, 1:7 and 1:9, and then are respectively placed in an autoclave.
(2) The temperature in each kettle is set to 45 ℃, carbon dioxide is introduced until the pressure reaches 25Mpa, the preparation time is 5 hours, the solid dispersion is taken out, and the crystal form is detected by an X-ray diffraction method after grinding.
(3) The detection result shows that ritonavir is amorphous in solid dispersion when the ratio of ritonavir to copovidone is 1:5-1:9.
TABLE 2 preparation of crystalline forms of solid dispersions at different temperatures
| Ritonavir and copovidone ratio | 1:1 | 1:3 | 1:5 | 1:7 | 1:9 |
| Crystalline form of ritonavir | Partial crystallization | Partial crystallization | Amorphous form | Amorphous form | Amorphous form |
Example 3 temperature for screening critical carbon dioxide to prepare solid Dispersion
The experimental process comprises the following steps:
(1) Ritonavir and copovidone were uniformly mixed in a ratio of 1:5, and then divided into 5 parts in average, wherein 4 parts were placed in an autoclave, respectively.
(2) Setting 35 ℃, 40 ℃, 45 ℃ and 50 ℃ respectively, introducing carbon dioxide respectively until the pressure reaches 25Mpa, taking out the solid dispersion after the preparation time is 5h, grinding, detecting the crystal form by adopting an X-ray diffraction method together with the mixture before the preparation of the solid dispersion, and detecting the acid hydrolysis impurity content by adopting an HPLC method. The test showed that the set temperature for preparing the solid dispersion should be 40-50 ℃.
(3) Preparing a solid dispersion by using a hot-melt extruder with an anisotropic conical screw, and mixing ritonavir and copovidone according to a ratio of 1:5, setting the rotating speed of the screw to 40rpm, the feeding rotating speed to 50rpm, the temperature of the first area to 40 ℃, the temperature of the second area to 100 ℃, the temperature of the third area to 120 ℃ and the temperature of the first area of the machine head to 120 ℃. The crystal form is detected by an X-ray diffraction method, and the content of acid hydrolysis impurities is detected by an HPLC method.
TABLE 3 Crystal forms and impurity conditions of solid dispersions prepared by different temperatures of critical carbon dioxide method and hot melt extrusion method
| Sample of | Crystalline form case | Acid hydrolysis of impurities (%) |
| Mixture before preparation of solid dispersion | Crystal form II | 0 |
| Preparing solid dispersion by setting 35 ℃ critical carbon dioxide method | Partial form II | 0 |
| Preparing solid dispersion by setting 40 ℃ critical carbon dioxide method | Amorphous form | 0 |
| Preparing solid dispersion by setting 45 ℃ critical carbon dioxide method | Amorphous form | 0 |
| Preparing solid dispersion by setting 50 ℃ critical carbon dioxide method | Amorphous form | 0 |
| Preparation of solid dispersion by hot melt extrusion | Amorphous form | 0.53 |
Example 4 investigation of the pressure of critical carbon dioxide
The experimental process comprises the following steps:
(1) Ritonavir and copovidone are uniformly mixed according to the proportion of 1:5, and are divided into 3 parts in average and are respectively placed in an autoclave.
(2) The temperature in each kettle is set to be 45 ℃, carbon dioxide is introduced until the pressure is 20, 25 and 30Mpa respectively, the preparation time is 5 hours, the solid dispersion is taken out, and the crystal form is detected by adopting an X-ray diffraction method after grinding.
(3) The detection result shows that ritonavir and copovidone are amorphous in solid dispersion when the ratio of ritonavir to copovidone is 20-30MPa.
Table 4 crystalline forms of ritonavir and copovidone in different ratios for preparing solid dispersion
| Pressure intensity | 20Mpa | 25Mpa | 30Mpa |
| Crystalline form of ritonavir | Amorphous form | Amorphous form | Amorphous form |
The foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of the invention should be assessed as that of the appended claims.
Claims (2)
1. A preparation method of ritonavir solid dispersion is characterized by uniformly mixing ritonavir and polyvinylpyrrolidone or copovidone according to a ratio of 1:5-1:9, placing the mixture in an autoclave, introducing carbon dioxide after the set temperature reaches 40-50 ℃ until the pressure reaches 20-30Mpa, maintaining the temperature and the pressure until the medicine and a carrier are dissolved, and collecting the mixture after depressurization to obtain the solid dispersion, wherein ritonavir in the solid dispersion is amorphous.
2. The method according to claim 1, wherein after obtaining the solid dispersion, the solid dispersion is crushed and passed through a 60-mesh sieve.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013024494A2 (en) * | 2011-08-18 | 2013-02-21 | Hetero Research Foundation | Amorphous mixture of lopinavir and ritonavir co-precipitated on copovidone |
| CN110354081A (en) * | 2019-08-01 | 2019-10-22 | 聊城高新生物技术有限公司 | The preparation method for the Ritonavir solid dispersions being precipitated in an aqueous medium can be reduced |
| WO2019219823A1 (en) * | 2018-05-18 | 2019-11-21 | Pharmaceutical Oriented Services Ltd. | Solid dispersion containing ritonavir |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050048112A1 (en) * | 2003-08-28 | 2005-03-03 | Jorg Breitenbach | Solid pharmaceutical dosage form |
| US8025899B2 (en) * | 2003-08-28 | 2011-09-27 | Abbott Laboratories | Solid pharmaceutical dosage form |
| EP2112925A4 (en) * | 2006-11-15 | 2013-01-09 | Abbott Lab | Solid pharmaceutical dosage formulations |
| WO2013080148A1 (en) * | 2011-11-28 | 2013-06-06 | Ranbaxy Laboratories Limited | A process for the preparation of solid dispersion of lopinavir and ritonavir |
| WO2014184553A1 (en) * | 2013-05-15 | 2014-11-20 | Cipla Limited | Pharmaceutical antiretroviral compositions |
| US10034865B2 (en) * | 2015-09-10 | 2018-07-31 | Kashiv Pharma, Llc | Surfactant-free HIV protease inhibitor composition and method of manufacturing thereof |
| CN108186578A (en) * | 2018-03-27 | 2018-06-22 | 聊城大学 | A kind of preparation method of Ritonavir solid dispersions |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013024494A2 (en) * | 2011-08-18 | 2013-02-21 | Hetero Research Foundation | Amorphous mixture of lopinavir and ritonavir co-precipitated on copovidone |
| WO2019219823A1 (en) * | 2018-05-18 | 2019-11-21 | Pharmaceutical Oriented Services Ltd. | Solid dispersion containing ritonavir |
| CN110354081A (en) * | 2019-08-01 | 2019-10-22 | 聊城高新生物技术有限公司 | The preparation method for the Ritonavir solid dispersions being precipitated in an aqueous medium can be reduced |
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